A. We are studying the molecular mechanisms by which estrogens and antiestrogens specifically alter growth of human breast cancer. 1. We have introduced viral onc genes (ras and myc) into human breast cancer cells. These retroviruses are stably integrated and viral mRNA is expressed at high levels. Ras induces a hormone independent phenotype. This occurs through increased secretion of several specific growth factors in an autonomous fashion. 2. We are using the technique of differential hybridization to identify specific estrogen regulated genes for cloning and subequent analysis. We have identified several unique genes induced within 6 hours by estradiol. We have also identified a gene which is specifically induced by antiestrogens and de-induced by estrogen stimulation. 3. We have identified and partially purified several estrogen induced growth factors which are secreted by breast cancer cells into the medium. Some of the activities cross react with EGF receptor and are candidate novel transforming growth factors. Purification and cDNA studies suggest that this TGFAlpha-like activity is not true TGFAlpha but a novel transforming action. Breast cancer cell lines are also secreting physiologically relevant concentrations of TGFABeta, IGF-1, a PDGF like competency factor and an epithelial growth factor. All of these activities are under intensive investigation.